Search

The emergence and rapid spread of SARS-CoV-2 variants may affect vaccine efficacy substantially. The Omicron variant termed BA.2, which differs substantially from BA.1 based on genetic sequence, is currently replacing BA.1 in several countries, but its antigenic characteristics have not yet been assessed. Here, we used antigenic cartography to quantify and visualize antigenic differences between early SARS-CoV-2 variants (614G, Alpha, Beta, Gamma, Zeta, Delta, and Mu) using hamster antisera obtained after primary infection. We first verified that the choice of the cell line for the neutralization assay did not affect the topology of the map substantially. Antigenic maps generated using pseudo-typed SARS-CoV-2 on the widely used VeroE6 cell line and the human airway cell line Calu-3 generated similar maps. Maps made using authentic SARS-CoV-2 on Calu-3 cells also closely resembled those generated with pseudo-typed viruses. The antigenic maps revealed a central cluster of SARS-CoV-2 variants, which grouped on the basis of mutual spike mutations. Whereas these early variants are antigenically similar, clustering relatively close to each other in antigenic space, Omicron BA.1 and BA.2 have evolved as two distinct antigenic outliers. Our data show that BA.1 and BA.2 both escape vaccine-induced antibody responses as a result of different antigenic characteristics. Thus, antigenic cartography could be used to assess antigenic properties of future SARS-CoV-2 variants of concern that emerge and to decide on the composition of novel spike-based (booster) vaccines. Coronavirus cartography: The emergence of new SARS-CoV-2 variants continues to initiate fresh waves of COVID-19 infection across the globe. Antigenic cartography is an established method for assessing the degree of antigenic difference based on the capacity of polyclonal antibodies to distinct viral variants to neutralize an array of related viruses. Mykytyn et al. applied antigenic cartography to SARS-CoV-2 variants by generating hamster antisera to individual variants and assessing their ability to neutralize variants up to Omicron BA.2. This analysis revealed Omicron BA.1 and BA.2 as outlier variants that are quite different from each other and a cluster of earlier SARS-CoV-2 variants. Analysis of cross-neutralization via antigenic cartography may be of value in making decisions on updating the spike antigen are used in future SARS-CoV-2 vaccines. [ABSTRACT FROM AUTHOR]

Tracking antiviral T cells in COVID-19: In patients infected with SARS-CoV-2, T lymphocytes stimulated by fragments of viral proteins contribute to immunity but may also promote the development of "cytokine storm." Weiskopf et al. studied the emergence of antiviral T cells in the blood of 10 patients with severe COVID-19 requiring ventilator treatment by stimulating blood lymphocytes with pools of peptides based on viral protein sequences. Peptide-reactive CD4+ and CD8+ T cells were already detectable at ICU admission and generally increased over time. Two of the 10 healthy controls responded weakly to the peptides, suggesting that some T cells induced by common cold coronaviruses can cross-react with SARS-CoV-2 antigens. These foundational studies set the stage for future experiments to tease apart the dynamics of T cell clones specific for different viral antigens. SARS-CoV-2 has been identified as the causative agent of a global outbreak of respiratory tract disease (COVID-19). In some patients, the infection results in moderate to severe acute respiratory distress syndrome, requiring invasive mechanical ventilation. High serum levels of IL-6 and IL-10, and an immune hyperresponsiveness referred to as a "cytokine storm," have been associated with poor clinical outcome. Despite the large numbers of COVID-19 cases and deaths, information on the phenotype and kinetics of SARS-CoV-2–specific T cells is limited. Here, we studied 10 patients with COVID-19 who required admission to an intensive care unit and detected SARS-CoV-2–specific CD4+ and CD8+ T cells in 10 of 10 and 8 of 10 patients, respectively. We also detected low levels of SARS-CoV-2–reactive T cells in 2 of 10 healthy controls not previously exposed to SARS-CoV-2, which is indicative of cross-reactivity due to past infection with "common cold" coronaviruses. The strongest T cell responses were directed to the spike (S) surface glycoprotein, and SARS-CoV-2–specific T cells predominantly produced effector and T helper 1 (TH1) cytokines, although TH2 and TH17 cytokines were also detected. Furthermore, we studied T cell kinetics and showed that SARS-CoV-2–specific T cells are present relatively early and increase over time. Collectively, these data shed light on the potential variations in T cell responses as a function of disease severity, an issue that is key to understanding the potential role of immunopathology in the disease, and also inform vaccine design and evaluation. [ABSTRACT FROM AUTHOR]

Measles infection prunes back B cell memory: Measles virus is a highly infectious lymphotropic virus associated with an extended period of immunosuppression after resolution of acute viremia. Petrova et al. sequenced the immunoglobulin gene repertoire of naïve and memory B cells in paired pre- and post-measles infection blood samples from unvaccinated children. Memory B cell clones present before infection were depleted in post-measles samples even after lymphocyte counts had recovered, a change not seen in controls given a flu vaccination. The naïve B cell repertoire exhibited multiple perturbations after measles infection, including a profound skew toward clones with immature features in ~10% of the cohort. The B cell repertoire changes documented in this study provide a molecular explanation for the durable "immune amnesia" observed after measles infection in unvaccinated populations. Measles is a disease caused by the highly infectious measles virus (MeV) that results in both viremia and lymphopenia. Lymphocyte counts recover shortly after the disappearance of measles-associated rash, but immunosuppression can persist for months to years after infection, resulting in increased incidence of secondary infections. Animal models and in vitro studies have proposed various immunological factors underlying this prolonged immune impairment, but the precise mechanisms operating in humans are unknown. Using B cell receptor (BCR) sequencing of human peripheral blood lymphocytes before and after MeV infection, we identified two immunological consequences from measles underlying immunosuppression: (i) incomplete reconstitution of the naïve B cell pool leading to immunological immaturity and (ii) compromised immune memory to previously encountered pathogens due to depletion of previously expanded B memory clones. Using a surrogate model of measles in ferrets, we investigated the clinical consequences of morbillivirus infection and demonstrated a depletion of vaccine-acquired immunity to influenza virus, leading to a compromised immune recall response and increased disease severity after secondary influenza virus challenge. Our results show that MeV infection causes changes in naïve and memory B lymphocyte diversity that persist after the resolution of clinical disease and thus contribute to compromised immunity to previous infections or vaccinations. This work highlights the importance of MeV vaccination not only for the control of measles but also for the maintenance of herd immunity to other pathogens, which can be compromised after MeV infection. [ABSTRACT FROM AUTHOR]

The severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is spreading rapidly, even in vaccinated individuals, raising concerns about immune escape. Here, we studied neutralizing antibodies and T cell responses targeting SARS-CoV-2 D614G [wild type (WT)] and the Beta, Delta, and Omicron variants of concern in a cohort of 60 health care workers after immunization with ChAdOx-1 S, Ad26.COV2.S, mRNA-1273, or BNT162b2. High binding antibody levels against WT SARS-CoV-2 spike (S) were detected 28 days after vaccination with both mRNA vaccines (mRNA-1273 or BNT162b2), which substantially decreased after 6 months. In contrast, antibody levels were lower after Ad26.COV2.S vaccination but did not wane. Neutralization assays showed consistent cross-neutralization of the Beta and Delta variants, but neutralization of Omicron was significantly lower or absent. BNT162b2 booster vaccination after either two mRNA-1273 immunizations or Ad26.COV2 priming partially restored neutralization of the Omicron variant, but responses were still up to 17-fold decreased compared with WT. SARS-CoV-2-specific T cells were detected up to 6 months after all vaccination regimens, with more consistent detection of specific CD4 + than CD8 + T cells. No significant differences were detected between WT- and variant-specific CD4 + or CD8 + T cell responses, including Omicron, indicating minimal escape at the T cell level. This study shows that vaccinated individuals retain T cell immunity to the SARS-CoV-2 Omicron variant, potentially balancing the lack of neutralizing antibodies in preventing or limiting severe COVID-19. Booster vaccinations are needed to further restore Omicron cross-neutralization by antibodies.

The emergence of SARS-CoV-2 variants harboring mutations in the spike (S) protein has raised concern about potential immune escape. Here, we studied humoral and cellular immune responses to wild type SARS-CoV-2 and the B.1.1.7 and B.1.351 variants of concern in a cohort of 121 BNT162b2 mRNA-vaccinated health care workers (HCW). Twenty-three HCW recovered from mild COVID-19 disease and exhibited a recall response with high levels of SARS-CoV-2-specific functional antibodies and virus-specific T cells after a single vaccination. Specific immune responses were also detected in seronegative HCW after one vaccination, but a second dose was required to reach high levels of functional antibodies and cellular immune responses in all individuals. Vaccination-induced antibodies cross-neutralized the variants B.1.1.7 and B.1.351, but the neutralizing capacity and Fc-mediated functionality against B.1.351 was consistently 2- to 4-fold lower than to the homologous virus. In addition, peripheral blood mononuclear cells were stimulated with peptide pools spanning the mutated S regions of B.1.1.7 and B.1.351 to detect cross-reactivity of SARS-CoV-2-specific T cells with variants. Importantly, we observed no differences in CD4 + T-cell activation in response to variant antigens, indicating that the B.1.1.7 and B.1.351 S proteins do not escape T-cell-mediated immunity elicited by the wild type S protein. In conclusion, this study shows that some variants can partially escape humoral immunity induced by SARS-CoV-2 infection or BNT162b2 vaccination, but S-specific CD4 + T-cell activation is not affected by the mutations in the B.1.1.7 and B.1.351 variants., (Copyright © 2021, American Association for the Advancement of Science.)

Containment of the COVID-19 pandemic requires reducing viral transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by membrane fusion between the viral and host cell membranes, which is mediated by the viral spike protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection and, on the basis of in vitro efficacy and in vivo biodistribution, selected a dimeric form for evaluation in an animal model. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour cohousing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and thus may readily translate into safe and effective intranasal prophylaxis to reduce transmission of SARS-CoV-2., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)